Combination Targeted Therapy with Chemo - 1254292

Hi shinbo,

I'm sorry to hear that your mother is not tolerating the trial drug, and that there is doubt about its efficacy.

The doctors here have addressed the issue of combining targeted therapies such as Xalkori with chemo. Dr. West has stated:

"There is interest in studying combinations of targeted therapies with other agents, including other targeted therapies and/or chemotherapy, to see if we can completely eradicate the cancer. Thus far, however, the answer has been no. People with an EGFR mutation who are treated with an EGFR tyrosine kinase inhibitor (TKI) respond very similarly to patients with an ALK rearrangement who receive crizotinib, and there have been trials combining EGFR TKI therapy with chemo in people with an EGFR mutation — these have not been curative and in general haven’t shown a clear benefit over the EGFR TKI alone. I would anticipate a similar pattern in people with an ALK rearrangement." http://cancergrace.org/lung/topic/can-xalkori-combine-with-other-drug-t…

It also seems that the combination being considered, in addition to Xalkori, is quite a bit to tolerate all at once. If your mother is having trouble with the trial drug, switching to Xalkori plus a three-drug combo which includes a platinum agent may be just as tough if not tougher.

It might be helpful to provide some information about your mother's prior treatments and whether she has had her cancer cells tested for the ALK rearrangement (which would indicate that Xalkori would be an especially appropriate drug for her).

Hope this helps.

JimC
Forum moderator

I'm sorry she's having such trouble tolerating LDK378.

I'd agree that there's really no meaningful amount of research yet on the combination of multiple chemotherapy agents with XALKORI (crizotinib). It's certainly a reasonable thing to consider, but there aren't data existing now to say whether that's likely to be a better choice than pursuing these treatments sequentially. The latter approach would likely have an easier side effect profile.

-Dr. West

FWIW, I have heard a couple of times from my fellow patients that their oncologist gave them a combo of chemo + Xalkori, but I've been wary of this concept.

My thought is that I'm under the impression that Xalkori (an ALK inhibitor) would make the Xalkori-sensitive cancer act more like normal lung tissue, so I'd wonder whether or not under Xalkori the chemo would have a fully potent effect against the inhibited cancer. You could ask your oncologist his/her thoughts on that.

For myself, I think I'd prefer my cancer act like cancer when I hit it with chemo, so it would drink up toxic poison in big gulps instead of small sips like normal cells do. So if I were in that situation, I'd probably want to discuss with my oncologist the pros & cons of taking a Xalkori break during the chemo, and then resume Xalkori afterwards, hoping that the chemo might crush at least the newer, smaller Xalkori-resistant cancer and maybe crush it all.

Best hopes,

Craig

Theoretical concerns and promises are best for considering what kind of clinical research is promising and ethical. When human life and well being is on the line, my strong opinion is that a theoretical advantage or concern should play a smaller role in off trial clinical considerations. Stated another way, basic science will help inform whether xalkori should be tried, in the context of a clinical trial, together with chemo. Until the vetting process has been done and such trials concluded, it would not be standard practice to try it outside of the context of a clinical trial. That said, it certainly wouldn't be crazy, but my bias lies with Dr. West's. Because I don't know that there would be a survival advantage to giving chemo and xalkori together, and because I know that side effects would be worse, I don't do this in practice. My personal philosophy is that quality of life is at least as important as duration of life. It's one thing to consider trading off some short term quality in exchange for increased duration; that's a matter of personal values. But, it's another thing to trade off quality for uncertain benefit for duration and even a chance of harm to it.

There's some limited information suggesting that patients with an ALK rearrangement may do particularly well with a heat shock protein (HSP90) inhibitor, as discussed briefly here:

http://cancergrace.org/lung/2012/07/09/ganetespib-phase2-kras-and-ldh/

I don't know of any data speaking to whether someone with an ALK rearrangement is more or less likely o benefit from an immunotherapy directed against anti-PD1 or anti-PDL1. I haven't seen any work speaking to that question.

Good luck.

-Dr. West

shinbo,

FWIW, last summer Dr. Ross Camidge did suggest that when I'm out of mutation-targeted drugs like Xalkori then an experimental HSP90 inhibitor like ganetespib might be something to look into. I think Dr. Shaw would agree, although maybe with a different HSP90 inhibitor. HSP90's are not necessarily easy drugs to tolerate, though. Chemo options would be the gamble with proven odds at this point, but I do hope to try an HSP90 inhibitor sooner or later, either alone or in combo with another targeted drug.

I was not aware of driving-mutation status being relevant to PD1/PDL1 expression levels (and therefore relevant to anti-PD1 drug trials). I thought they were independent attributes. What specifically have you heard about EGFR and what was the source of that information?

I did hear you needed to test the cancer for PD1/PDL1 levels to be know whether there is a chance of benefit. The early data on the BMS anti-PD1 drug made me think it might work better for squamous cell lung cancer than non-squamous NSCLC. I heard a couple of good anecdotal reports from people on MK-3475, so I'm looking forward to seeing better data on both of them and I hope I will try (sooner or later) whichever one seems to have the best odds of good duration for cancer more like mine.

Best hopes,

Craig

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P.S. -- Thanks, Dr. West, for the reminder of your HSP90 inhibitor ganetespib discussion for ALK+'s. Small numbers of people, but compelling for them; hopefully it'll hold up with more patients as the trial expands.